Molecular Mechanisms of Iron Uptake by Cells and the Use of Iron Chelators for the Treatment of Cancer

Abstract

The field of iron (Fe) metabolism has been invigorated in the past 10 years with the discovery of a variety of new molecules involved in the homeostatic control of this critical nutrient. These proteins include the transferrin receptor 2, frataxin, hephaestin, hepcidin, hemojuvelin and others. Basic understanding of the metabolism of Fe in cells is vital in order to develop Fe chelators for the treatment of a variety of disease states. In addition, examination of the role of Fe in the regulation of cell cycle progression and angiogenesis has led to investigations of the use of novel Fe chelators as anti-proliferative agents. These studies have resulted in the identification of new ligands that show selective and potent anti-tumor activity in vitro and in vivo. Moreover, the ability of these chelators to inhibit growth is not only limited to the inhibition of DNA synthesis. In fact, there is a range of targets that are affected by Fe-depletion, such as molecules involved in cell cycle control, angiogenesis and metastasis suppression. These include hypoxia-inducible factor-1 alpha (HIF-1 alpha), vascular endothelial growth factor-1 (VEGF1), p21(CIP1/WAF1), cyclin D1 and the protein product of the N-myc downstream regulated gene-1 (Ndrg1). As such, Fe chelators can now be designed to target molecules to induce specific effects, for instance, angiogenesis or metastasis suppression.

Cellular Iron Depletion Stimulates the JNK and p38 MAPK Signaling Transduction Pathways, Dissociation of ASK1-Thioredoxin, and Activation of ASK1

“…1E). The alteration of VEGF signaling is in agreement with the well known effect of iron depletion on the up-regulation of VEGF expression (35,36). Incubation of cells with Dp44mT also affected the expression of the mTOR, Jak-STAT, and TGF-␤-signaling pathways, although DFO did not.…”

A class of iron chelators with a wide spectrum of potent antitumor activity that overcomes resistance to chemotherapeutics

“…Fe is crucial for proliferation, and studies in vitro have demonstrated that chelators up-regulate the expression of Fe-responsive genes such as the TfR1, which is involved in Fe uptake; VEGF1, which plays a role in angiogenesis; and the tumor growth and metastasis suppressor gene Ndrg1 (12,23). To understand the molecular events after Fe chelation, we performed RT-PCR examining the mRNA expression of Ndrg1, TfR1, and VEGF1 in the liver (Fig.…”

Nitric Oxide Suppresses Tumor Cell Migration Through N-Myc Downstream Regulated Gene-1 (NDRG1) Expression: the Role of Chelatable Iron

“…Of these biological targets, one of the potentially most significant and least studied is the chelatable iron pool (CIP). This small, but chemically significant, fraction of total cellular iron (0.2-3.0%, low M range) (31, 32) is methodologically defined because it is accessible to chemical iron chelators (33). More importantly, it has recently been demonstrated that when cells are exposed to ⅐ NO, the CIP is quantitatively converted into paramagnetic dinitrosyliron complexes with thiolcontaining ligands (DNIC) (34,35).…”